1-piperazinoisoquinolines as inotropic agents

ABSTRACT

Certain 1-piperazinoisoquinolines, e.g., 1-(4methylpiperazinyl)-6,7-dimethoxyisoquinoline, are useful as positive inotropic agents.

United States Patent 1191 Simpson 1451 Dec. 31, 1974 1-PIPERAZINOISOQUINOLINES AS INOTROPIC AGENTS Related US. Application Data [63] Continuation-impart of Ser. No. 246,321, April 21,

1972, abandoned.

[52] US. Cl. 424/250 [51] Int. Cl A61k 27/00 [58] Field of Search 424/250 [56] 1 References Cited UNITED STATES PATENTS 3,594,480 7/1971 Cronin et al 424/250 Primary Examiner-Jerome-D. Goldberg Attorney, Agent, or Firm-Gerald D. Sharkin; Robert S. Honor; Thomas O. McGovern [57] ABSTRACT Certain l-piperazinoisoquinolines, e.g., l-(4- methylpiperazinyl)-6,7-dimethoxyisoquinoline, are useful as positive inotropic agents. v

-7 Claims, No Drawings formula:

R1 \Ra \l/ l j R 1 14 where R and R each independently represent hydrogen,

hydroxy, lower alkyl, i.e., alkyl having 1 to 6 carbon atoms, e.g., methyl, ethyl, isopropyl and the like, or lower alkoxy i.e., alkoxy having 1 to carbon atoms, e.g., methoxy, ethoxy, isopropoxy and the like, or

R, and R together represent alkylenedioxy having 1 to 4 carbon atoms, e.g., methylenedioxy, ethylenedioxy, propylenedioxy and the like or together with the carbon atoms to which they are attached they represent a fused benzene ring;

R is hydrogen or lower alkyl as defined above, and

R is hydrogen; lower alkylas defined above; alkenyl having 3 to 6 carbon atoms, e.g., allyl, 4-hexen-2 yl and the like; unsubstituted aryl having 6 to 10 carbon atoms, e.g., phenyl, tolyl, xylyl, napthyl, and

' the like or aryl having 6 to 10 carbon atoms mono or di-substituted with alkoxy as defined above, fluorine or chlorine; alkanoyl having 2 to 6 carbon atoms, e.g,, acetyl, propionyl, isobutyryl, and the like; aroyl having 7 to 11 carbon atoms, e.g., benzoyl, toloyl, naphthoyl, and the like; or aroyl having 7 to ll carbon atoms mono or di-substituted with alkoxy as defined above, fluorine or chlorine carbalkoxy having 2 to 7 carbon atoms, e,g., carbomethoxy, carbethoxy carbisopropoxy and the like; carbalkenyloxy having 4 to 7 carbon atoms, e.g., carballyloxy, carbo-4-methyl-Z-pentenyloxy and the like or carbaryloxy having 7 to l 1 carbon atoms, e.g., carbobenzoxy, .carbotolyloxy, carbonaphthoxy and the like and pharmaceutically acceptable acid addition salts thereof, provided that only one of R and R is tertiary alkyl having the tertiary carbon atoms bonded to the aromatic nucleus or tertiary alkoxy where the tertiary carbon atom is attached to the oxygen atom.

. The compounds of formula (1) above are known and may be prepared according to methods disclosed in the literature from known materials, for example, as described in Examples LV and LVI of US. Pat. No. 3,594,480. The present invention contemplates only the novel use of such compounds in pharmaceutical applications, in particular, as positive inotropic agents on cardiac muscle in the treatment of myocardial shock.

As indicated above, the compounds of formula (I) are useful in animals as positive inotropic agents as indicated by increased cardiac contractability as measured in anesthetized dogs using a Walton Brodie strain gage. The dog is anesthetized with 30 milligrams per kilogram (30 mg/kg) i.v. of pentobarbital sodium, i.v. Blood pressure is recorded with a transducer via tubing inserted into a femoral artery. A cannula is placed in the contralateral femoral vein for drug administration. The trachea is isolated, divided and cannulated with tubing from a Harvard air pump in order to maintain respiration. A left thorocotomy is performed between the 4th and 5th intercostal spaces and the opening in the chest widened with retractors. The pericardium is opened and the edges sewn to the chest opening to form a cradle for the heart. Care must be taken not to cut the phrenic nerve which runs along the-pericardium. A segment of the left anterior descending artery is isolated. The coronary artery is litigated and the distal portion of the artery cannulated with tubing which carries blood from the central stump of a previously cannulated carotid artery. Blood flow is measured electronically. The Walton Brodie strain gage arch is then sewn to the portion ofthe myocardium perfused by the cannulated coronary artery. The opening in the chest is then covered with gauze pads which have been saturated with saline.

Heart rate is measured with either a tachometer driven by the contractile force signal or by that of the electrocardiogram. Rectal temperature is monitored, and body temperature are maintained by an electric heating pad which has previously been placed under the animal.

Before administration of a test compound the hyperemia reflex is tested by occluding the coronary flow for 20 seconds. Twenty micrograms per kiologram of animal body weight nitroglycerine (20mcg/kg) is administered i.v. as a reference agent. The compound to be tested is administered in doses of().l, L0, 5.0 and l0,0 mg/kg i.v. Suitable solvent controls are performed as necessary. The test compound, if active by the i.v. route, can also be tested by direct intra-arterial injection into the tubing leading to the coronoary artery. All parameters are recorded either with a Sanborn or a Grass polygraph.

For such usage, the compounds may be administered orally or parenterally as such or admixed with conventional pharmaceutical carriers. They may be administered in such forms as tablets, dispersible powders, granules, capsules, syrups and elixirs and parenterally as solutions, suspensions, dispersions, emulsions and the like, e.g., a sterile injectable aqueous solution. The compositions may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutically acceptable excipients, e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents,

e.g., starch, gelatin and acacia, and lubricating agents,

e.g., magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated byknown techniques to delay disintetration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Similarly, oral liquids, e.g., suspensions may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate) wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan mono-oleate) and preservatives (ethyl-o-hydroxybenzoate). Capsules may contain the active ingredient alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin. The injectable compositions are formulated as known in the art. These pharmaceutical preparations may contain up to about 90 percent of the active ingredient in combination with the carrier or adjuvant.

Furthermore, the compounds of formula (I) may be similarly administered in the form of their non-toxic pharmaceutically acceptable acid addition salts. Suchsalts possess the same order of activity as the free base, are readily prepared by reacting the base with an appropriate acid, and,,accordingly,'are included within the scope of the invention. Representative of such salts are the mineral acid salts, such as the hydrochloride, hydrobromide sulfate, phosphate and the like and the organic acid salts, such as the succinate, benzoate, acetate, p-toluenesulfonate, benzene-sulfonate, maleate, malate, tartrate, methanesulfonate, cyclohexylsulfamate and the like.

The positive inotropic effective dosage of the compound of formula (I) employed in the alleviation of myocardial shock in cardiac muscle may vary depending on the particular compound employed, the manner of administering and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of formula (I) are administered at a daily dosage of from about 0.0001 milligrams to about milligrams per kilogram of animal body weight i.v. or, for prophylactic use, 0.1 milligrams to 200 milligrams per kilogram of animal body weight p.o. The compounds are given in a single dose i.v. as needed (p.r.n.); and orally, they are preferably given in divided doses two to four times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 01 milligrams to about 10 milligrams p.r.n. i.v. or, prophylactically, l milligram to 500 milligrams p.o. Dosage forms suitable for prophylactic oral use comprise from about 0.25 to about 250 milligrams of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

Compounds of formula (I) in addition to the previously mentioned preferred compound which can be used as the active ingredient include the following:

I. l-(4-methyl-l-piperazinyl)-7-hydroxy-6-methoxy-3- methylisoquinoline, 2. l-(4-[2-propyl]-l-piperazinyl)- 6-hydroxy-7-methoxyisoquinoline; 3. l-piperazinyl- 6,7-dihydroxy-3methylisoquinoline;

4. l-(4-hexyl-l-piperazinyl)-7-methoxy-6- methylisoquinoline;

5. l-(4-allyl-l-piperazinyl)-7-methoxyisoquinoline;

6. l-(4-[4-hepten-2-yl]-l-piperazinyl)-6,7- dimethoxyisoquinoline;

7. l-(4-phenyl-l-piperazinyl)-6,7- dimethylisoquinoline; 8. l-(4I m-tolyl l -piperazinyl )-7-hydroxy-6- ethoxyisoquinoline;

9. 1-(4-[5-propyl-3-tolyl]-l-piperazinyl)-7-hydroxy-6- methoxy-3-methylisoquinoline;

l0. l-(4-[p-chlorophenyl1-l-piperazinyl)-6,7- dimethoxyisoquinoline;

ll. l-(4-[p-fluorophenyl]-l-piperazinyl)-6,7- dimethoxyisoquinoline;

l2. l-(4-[4-tertiarybutoxyphenyl]-l-piperazinyl)-6,7- dimethoxyisoquinoline;

l3. l-(4-naphthyll -piperazinyl )-7-hydroxy-6- methoxyisoquinoline;

l4. l-(4-carballyloxy-l-piperazinyl)-6-hydroxy-7- methoxyisoquinoline;

l5. 1-(4-carbo-[2-methyl-penten-3-oxy]lpiperazinyl)-benz[g] isoquinoline;

16. l-(4-carbobenzoxy-l-piperazinyl)-6,7-dihydroxy- 3-methylisoquinoline;

l7, l-(4-[carbo-2,5-dimethylbenzoxy]-l-piperazinyl)- 7-hydroxy-6-methoxy-3methylisoquinoline;

l8. l-(4-[carbo-3-methyl-5-propyl-benzoxy1- l piperazinyl)-7-hydroxy-6-methoxy-3- methylisoquinoline;

l9. l-(4-carbo[3-naphthoxy-l-piperazinyl)-7-hydroxy- 6-methoxy-3-methylisoquinoline;

20. dimethoxyisoquinoline; 21. l-(4-isobutyryll -piperazinyl)-6-methoxy-3,7- dimethylisoquinoline;

22. l-(4-valeryl-l-piperazinyl)-7-hydroxy-6- ,ethoxyisoquinoline;

23. l-(4-benzoyl-l-piperazinyl)-benz[g]isoquinoline; 24. l-(4-[p-chlorobenzyl1-l-piperazinyl)-6,7- dimethoxyisoquinoline;

25. l-(4-[p-fluorobenzoyl]-l-piperazinyl)-6,7- dimethoxyisoquinoline;

26. l-(4-[p-methoxybenzoyl1-l-piperazinyl)-6,7- dimethoxyisoquinoline;

27. l-(4-m-toloyl-l-piperazinyl)-6,7- propylenedioxyisoquinoline;

28. l-(4-[2-methyl-5-propylbenzoyl]-l-piperazinyl)-7- hydroxy-6-methoxy-3-methylisoquinoline;

29. l-(4-naphthoyl-l-piperazinyl)-7- methoxyisoquinoline;

30. l-(4-carbomethoxy-l-piperazinyl)-6,7- dimethoxyisoquinoline;

3 l. l-(4-carbisopropoxyl -piperazinyl )-6,7- dimethoxyisoquinoline and 32. l-(4-carbovaleryloxy-l-piperazinyl)-6,7- dimethoxyisoquinoline.

The preferred compositions for prophylactic use from the standpoint of preparation and ease of administration are solid compositions, particularly hard-filled capsules and tablets containing from about 5 to 50 milligrams of the active ingredient.

EXAMPLES 1 AND 2 Tablets and Capsules Suitable For Oral Administration Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful positive inotropic agents at a dose of one tablet or capsule 2 to 4 times a day.

l-(4-acetyll -piperazinyl )-6,7-

j where lngredem Weigh! R and R each independently represent hydrogen,

- hydroxy lower alkyl or lower alkoxy or l-(4-methyll-piperazinyl)-6,7- tablet capsule dimcthoxyisoquinohne R, and R together represent alkylenedioxy having 1 tragacanth 10 to 4 carbon atoms or together with the carbon lactose 2375 290 atoms to which they are attached they represent corn starch 25 f talcum 5 used benzene, magnesium stearate 2.5 R3 is hydrogen OI lower alkyl and Total 300 s 300 s R is hydrogen, lower alkyl, alkenyl having 3 to 6 carbon atoms, aryl having 6 to 10 carbon atoms, aryl I having 6 to 10 carbon atoms mono or dil and Capsules uscful h l f of y substituted with lower alkoxy, fluorine or chlorine, cai'dial shock may he prepared in a similar manner lk h i 2 to 6 carbon atoms, aroyl having using compounds 1 to 32 above as the active ingredi 7 to 11 carbon atoms or aroyl having 7 to ll carent. bon atoms, mono or di-substituted with lower alk- EXAMPLES 3 AND 4 oxy, fluorine or chlorine, carbalkoxy having 2 to 7 carbon atoms, carbalkenyloxy having 4 to 7 carbon Sterile Suspension for Injection and Oral Liquid Susatoms Or carbaryloxy having 7 I0 11 Carbon alOmS pension 0r The following pharmaceutical compositions are fora pharmaceutieally acceptable acid addition salt 2O mulated with the Indicated amount of active agent thereof, provided that only one of R and R is tertiary using conventional techniques. The injectable suspeny l g h ternary Carbon atom bQIIdEd to sion and the oral liquid suspension represent formula- Omatlc nucleus or tfirmly alkoxy having the ternary tions useful as unit doses which may be administered as Carbon atom attached to the Oxygen atompo sitive inotropic agents The injectable suspension is 2 A h d ding t claim 1 in which R and R suitable for adm nistration iv. (p.r.n. once a day h i d d l represent hydrogen, h d whereas the oral liquid suspension is suitable adminis methoxy or methyl, R is hydrogen and R is hydrogen tered 2 to 4 times per day for this purpose. or lower alkyl having 1 to 4 carbon atoms. I

Ingredients Weight (mg) injectable liquid suspension suspension l-(4-methyl-l-piperazinyl)-6,7- dimethoxyisoquinoline 5 10 sodium carboxy methyl cellulose U.S.P. 1.25 12.5 methyl cellulose 0.4 polyvinylpyrrolidone 5 lecithin 3 benzyl alcohol 0.01 magnesium aluminum silicate 47.5 flavor q.s. color q.s. mathyl paraben, U.S.P. 4.5 propyl paraben, U.S.P. 1.0 polysorbate 80 (cg. Tween 80), USP 5 sorbitol solution, 70%, USP 2,500 buffer agent to adjust pH for desired stability q.s. q.s. water for injection, q.s. to 5 ml q.s. to 1 ml Similarly, injectable suspensions and oral liquid sus- 3. A method according to claim 1 in which R, and R pension useful in the treatment of mycardial shock may are methoxy, R is hydrogen and R is lower alkyl havbe prepared in the same manner using compound 1 to ing 1 to 4carbon atoms. I 1 32 as h m mgmdlem- 4. A method according to claim 1 wherein the comwhat Clalmed pound is administered intravenously at a daily dosage l. A method of r g myocardlal Shock whlcll of from about 0.01 milligrams to about 10 milligrams. comprises administering to a mammal in need of said Y treatment an effective amount for the treatment ofm 55 A method accordmg to claim 1 wherem the com- Ocardial shock of a Com ound of the formula pound is administered orally at a daily dosage of from p about 1 milligram to about 500 milligrams.

6. A method according to claim 1 wherein the com- R1 fi-R pound is orally administered in a unit dosage form comrisin said com ound to the extent of from about 0.25 N P g P R: milligrams to about 250 milligrams per unit dosage.

l 7. A method according to claim 1 in which the compound is l-(4-methyl-l-piperazinyl)-6,7- l dimethoxyisoquinoline.

l =l =l 

1. A METHOD OF TREATING MYOCARDIAL SHOCK WHICH COMPRISES ADMINISTERING TO A MAMMAL IN NEED OF SAID TREATMENT AN EFFECTIVE AMOUNT FOR THE TREATMENT OF MYOCARDIAL SHOCK OF A COMPOUND OF THE FORMULA:
 2. A method according to claim 1 in which R1 and R2 each independently represent hydrogen, hydroxy, methoxy or methyl, R3 is hydrogen and R4 is hydrogen or lower alkyl having 1 to 4 carbon atoms.
 3. A method according to claim 1 in which R1 and R2 are methoxy, R3 is hydrogen and R4 is lower alkyl having 1 to 4 carbon atoms.
 4. A method according to claim 1 wherein the compound is administered intravenously at a daily dosage of from about 0.01 milligrams to about 10 milligrams.
 5. A method according to claim 1 wherein the compound is administered orally at a daily dosage of from about 1 milligram to about 500 milligrams.
 6. A method according to claim 1 wherein the compound is orally administered in a unit dosage form comprising said compound to the extent of from about 0.25 milligrams to about 250 milligrams per unit dosage.
 7. A method according to claim 1 in which the compound is 1-(4-methyl-1-piperazinyl)-6,7-dimethoxyisoquinoline. 